The lack of technology to rapidly, accurately and cost-effectively assess mutagenic outcomes in humans has essentially constrained a more complete understanding of individual susceptibility to environmental mutagens and their relationship to cancer, genetic disease and aging. An assay to measure mutation frequency and spectrum directly in human blood or tissue samples would provide information about previous exposures to environmental mutagens in relation to the status of an individual's diverse array of genome maintenance pathways. This would enable human population-based studies, clinical studies and routine biomonitoring for risk assessment. Here we propose to develop a highly sensitive, robust and scalable assay for directly measuring DNA mutations in human cells or tissues by sequence capture and massively parallel sequencing (SC-MPS). PUBLIC HEALTH RELEVANCE: Humans are exposed to a large variety of environmental mutagens and carcinogens. We propose to develop a method that allows measuring DNA mutation load in human blood or tissue samples directly, without selection. This should provide a robust and cost-effective assay to assess individual human risk, for example, after possible exposure to mutagens.